Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling

Astrocytes and microglia are both known to regulate synapse remodeling, but it remains unclear how these two cell types communicate to coordinate this process in response to changes in neural activity. This study investigates the crosstalk between microglia and astrocytes during activity-dependent synapse removal in the mouse barrel cortex following whisker lesioning.

Using a whisker removal model in postnatal mice, the authors combined cell-type-specific translating ribosome affinity purification (TRAP-seq) with expansion microscopy and electron microscopy to observe structural changes at the synapse. They employed molecular genetic tools—including astrocyte-specific APC knockout and microglia-specific Wntless (Wls) knockout—to manipulate signaling pathways. Spatial transcriptomics (MERFISH) and in vitro astrocyte culture systems were used to identify the specific molecular mediators of microglia-astrocyte communication.

Whisker lesioning induces a progressive reduction in the physical association between astrocyte processes and thalamocortical synapses, which precedes microglial synapse engulfment. This process is not driven by astrocyte phagocytosis, but rather by microglia-derived Wnt ligands. Microglia release Wnts downstream of neuronal fractalkine (CX3CL1-CX3CR1) signaling, which activates canonical Wnt signaling in astrocytes. This activation is sufficient to induce the retraction of astrocyte processes from synapses. Blocking Wnt release from microglia prevents this astrocyte retraction and subsequently inhibits microglial synapse engulfment and synapse loss, demonstrating that this crosstalk is a critical regulatory step in activity-dependent circuit remodeling.

This study reveals a novel, activity-dependent mechanism of glia-glia communication that coordinates synaptic pruning. By identifying Wnt signaling as a key mediator, the authors provide a potential framework for understanding how synapse remodeling is regulated in both physiological development and disease states, such as Alzheimer’s disease and epilepsy, where similar astrocyte-synapse interactions and Wnt signaling signatures have been observed.